Pages

Search This Blog

Friday, February 28, 2014

A tug-of-war between driver and passenger mutations in cancer and other adaptive processes

Christopher DennisMcFarland, Leonid AMirny, Kirill SKorolev

doi: 10.1101/003053

Abstract

Cancer
progression is an example of a rapid adaptive process where evolving
new traits is essential for survival and requires a high mutation rate.
Precancerous cells acquire a few key mutations that drive rapid
population growth and carcinogenesis. Cancer genomics demonstrates that
these few driver mutations occur alongside thousands of random
passenger mutationsa natural consequence of cancer's elevated
mutation rate. Some passengers can be deleterious to cancer cells, yet
have been largely ignored in cancer research. In population genetics,
however, the accumulation of mildly deleterious mutations has been shown
to cause population meltdown. Here we develop a stochastic population
model where beneficial drivers engage in a tug-of-war with frequent
mildly deleterious passengers. These passengers present a barrier to
cancer progression that is described by a critical population size,
below which most lesions fail to progress, and a critical mutation rate,
above which cancers meltdown. We find support for the model in cancer
age-incidence and cancer genomics data that also allow us to estimate
the fitness advantage of drivers and fitness costs of passengers. We
identify two regimes of adaptive evolutionary dynamics and use these
regimes to rationalize successes and failures of different treatment
strategies. We find that a tumors load of deleterious passengers can
explain previously paradoxical treatment outcomes and suggest that it
could potentially serve as a biomarker of response to mutagenic
therapies. The collective deleterious effect of passengers is currently
an unexploited therapeutic target. We discuss how their effects might be
exacerbated by both current and future therapies.

Cancer-driven dynamics of immune cells in a microfluidic environment

Scope of the present work is to frame into a rigorous, quantitative scaffold
- stemmed from stochastic process theory - two sets of experiments designed to
infer the spontaneous organization of leukocytes against cancer cells, namely
mice splenocytes vs. B16 mouse tumor cells, and embedded in an "ad hoc"
microfluidic environment developed on a LabOnChip technology. In the former,
splenocytes from knocked out (KO) mice engineered to silence the transcription
factor IRF-8, crucial for the development and function of several immune
populations, were used. In this case lymphocytes and cancer cells exhibited a
poor reciprocal exchange, resulting in the inability of coordinating or
mounting an effective immune response against melanoma. In the second class of
tests, wild type (WT) splenocytes were able to interact with and to coordinate
a response against the tumor cells through physical interaction. The
environment where cells moved was built of by two different chambers,
containing respectively melanoma cells and splenocytes, connected by capillary
migration channels allowing leucocytes to migrate from their chamber toward the
melanoma one. We collected and analyzed data on the motility of the cells and
found that the first ensemble of IRF-8 KO cells performed pure uncorrelated
random walks, while WT splenocytes were able to make singular drifted random
walks, that, averaged over the ensemble of cells, collapsed on a straight
ballistic motion for the system as a whole. At a finer level of investigation,
we found that IRF-8 KO splenocytes moved rather uniformly since their step
lengths were exponentially distributed, while WT counterpart displayed a
qualitatively broader motion as their step lengths along the direction of the
melanoma were log-normally distributed.

Wednesday, February 5, 2014

Evolutionary dynamics of shared niche construction

Many species engage in niche construction that ultimately leads to an
increase in the carrying capacity of the population. We have investigated how
the specificity of this behaviour affects evolutionary dynamics using a set of
coupled logistic equations, where the carrying capacity of each genotype
consists of two components: an intrinsic part and a contribution from all
genotypes present in the population. The relative contribution of the two
components is controlled by a specificity parameter $\gamma$, and we show that
the ability of a mutant to invade a resident population depends strongly on
this parameter. When the carrying capacity is intrinsic, selection is almost
exclusively for mutants with higher carrying capacity, while a shared carrying
capacity yields selection purely on growth rate. This result has important
implications for our understanding of niche construction, in particular the
evolutionary dynamics of tumor growth.